tbuckley/cabot-search huggingface dataset:
Tarlatamab for Patients with Previously Treated Small-Cell Lung Cancer
Authors: Myung-Ju Ahn, Byoung Chul Cho, Enriqueta Felip, Ippokratis Korantzis, Kadoaki Ohashi, Margarita Majem, Oscar Juan-Vidal, Sabin Handzhiev, Hiroki Izumi, Jong-Seok Lee, Rafal Dziadziuszko, Jürgen Wolf, Fiona Blackhall, Martin Reck, Jean Bustamante Alvarez, Horst-Dieter Hummel, Anne-Marie C. Dingemans, Jacob Sands, Hiroaki Akamatsu, Taofeek K. Owonikoko, Suresh S. Ramalingam, Hossein Borghaei, Melissa L. Johnson, Shuang Huang, Sujoy Mukherjee, Mukul Minocha, Tony Jiang, Pablo Martinez, Erik S. Anderson, Luis Paz-Ares
Journal: New England Journal of Medicine (2023)

Tarlatamab, a bispecific T-cell engager immunotherapy targeting delta-like ligand 3 and CD3, showed promising antitumor activity in a phase 1 trial in patients with previously treated small-cell lung cancer.In this phase 2 trial, we evaluated the antitumor activity and safety of tarlatamab, administered intravenously every 2 weeks at a dose of 10 mg or 100 mg, in patients with previously treated small-cell lung cancer. The primary end point was objective response (complete or partial response), as assessed by blinded independent central review according to the Response Evaluation Criteria in Solid Tumors, version 1.1.Overall, 220 patients received tarlatamab; patients had previously received a median of two lines of treatment. Among patients evaluated for antitumor activity and survival, the median follow-up was 10.6 months in the 10-mg group and 10.3 months in the 100-mg group. An objective response occurred in 40% (97.5% confidence interval [CI], 29 to 52) of the patients in the 10-mg group and in 32% (97.5% CI, 21 to 44) of those in the 100-mg group. Among patients with an objective response, the duration of response was at least 6 months in 59% (40 of 68 patients). Objective responses at the time of data cutoff were ongoing in 22 of 40 patients (55%) in the 10-mg group and in 16 of 28 patients (57%) in the 100-mg group. The median progression-free survival was 4.9 months (95% CI, 2.9 to 6.7) in the 10-mg group and 3.9 months (95% CI, 2.6 to 4.4) in the 100-mg group; the estimates of overall survival at 9 months were 68% and 66% of patients, respectively. The most common adverse events were cytokine-release syndrome (in 51% of the patients in the 10-mg group and in 61% of those in the 100-mg group), decreased appetite (in 29% and 44%, respectively), and pyrexia (in 35% and 33%). Cytokine-release syndrome occurred primarily during treatment cycle 1, and events in most of the patients were grade 1 or 2 in severity. Grade 3 cytokine-release syndrome occurred less frequently in the 10-mg group (in 1% of the patients) than in the 100-mg group (in 6%). A low percentage of patients (3%) discontinued tarlatamab because of treatment-related adverse events.Tarlatamab, administered as a 10-mg dose every 2 weeks, showed antitumor activity with durable objective responses and promising survival outcomes in patients with previously treated small-cell lung cancer. No new safety signals were identified. (Funded by Amgen; DeLLphi-301 ClinicalTrials.gov number, NCT05060016.).
Phase III, Randomized Study of Atezolizumab Plus Bevacizumab and Chemotherapy in Patients With <i>EGFR</i>- or <i>ALK</i>-Rearranged or Translocated Non–Small-Cell Lung Cancer (ATTLAS, KCSG-LU19-04)
Authors: Sehhoon Park, Tae Min Kim, Ji-Youn Han, Gyeong-Won Lee, Byoung Yong Shim, Yun-Gyoo Lee, Sang-We Kim, Il Hwan Kim, Suee Lee, Yu Jung Kim, Ji Hyun Park, Sang-Gon Park, Ki Hyeong Lee, Eun Joo Kang, Ju Won Kim, Seong-Hoon Shin, Chan-Young Ock, Byung-Ho Nam, Jaebong Lee, Hyun-Ae Jung, Jong-Mu Sun, Se-Hoon Lee, Jin Seok Ahn, Myung-Ju Ahn
Journal: Journal of Clinical Oncology (2023)

PURPOSE In the treatment of non–small-cell lung cancer (NSCLC) with a driver mutation, the role of anti–PD-(L)1 antibody after tyrosine kinase inhibitor (TKI) remains unclear. This randomized, open-label, multicenter, phase III study evaluates the efficacy of atezolizumab plus bevacizumab, paclitaxel, and carboplatin (ABCP ) in EGFR- or ALK-rearranged or translocated NSCLC upon progression on TKI therapy. MATERIALS AND METHODS We compared the clinical efficacy of ABCP followed by maintenance therapy with atezolizumab plus bevacizumab with pemetrexed plus carboplatin or cisplatin (PC) followed by pemetrexed maintenance. The primary end point was progression-free survival (PFS). RESULTS A total of 228 patients with activating EGFR mutation (n = 215) or ALK translocation (n = 13) were enrolled from 16 sites in the Republic of Korea and randomly assigned at 2:1 ratio to either ABCP (n = 154) or PC arm (n = 74). The median follow-up duration was 26.1 months (95% CI, 24.7 to 28.2). Objective response rates (69.5% v 41.9%, P &lt; .001) and median PFS (8.48 v 5.62 months, hazard ratio [HR], 0.62 [95% CI, 0.45 to 0.86]; P = .004) were significantly better in the ABCP than PC arm. PFS benefit increased as PD-L1 expression increased, with an HR of 0.47, 0.41, and 0.24 for PD-L1 ≥1%, ≥10%, and ≥50%, respectively. Overall survival was similar between ABCP and PC arm (20.63 v 20.27 months, HR, 1.01 [95% CI, 0.69 to 1.46]; P = .975). The safety profile of the ABCP arm was comparable with that previously reported, with no additional safety signals, but higher rates of treatment-related adverse events were observed compared with the PC arm. CONCLUSION To our knowledge, this study is the first randomized phase III study to demonstrate the clinical benefit of anti–PD-L1 antibody in combination with bevacizumab and chemotherapy in patients with EGFR- or ALK-rearranged or translocated NSCLC who have progressed on relevant targeted therapy.
Tumor microenvironment‐dependent epigenetic imprinting in the vasculature predicts colon cancer outcome
Authors: Elisabeth Naschberger, Maximilian Fuchs, Nicholas Dickel, Meik Kunz, Bernt Popp, Charles Gwellem Anchang, Richard Demmler, Yanmin Lyu, Steffen Uebe, Arif Bülent Ekici, Carol Immanuel Geppert, Arndt Hartmann, Christian Flierl, Katja Petter, Tobias Gass, Simon Völkl, Michael Scharl, Andreas Ramming, Claudia Günther, Susanne Merkel, Vera Simone Schellerer, Michael Stürzl
Journal: Cancer Communications (2023)

Tumor microenvironment-dependent epigenetic imprinting in the vasculature predicts colon cancer outcomeDear Editor,Tumor microenvironment (TME)-dependent stromal cell plasticity governs tumor development and therapy response.Tumor endothelial cells (TECs) are a major cellular component in this context [1].In colorectal carcinoma (CRC), the stromal cell-dependent impact of the TME is illustrated by an improved survival depending on an interferon (IFN)-γ-dominated Th1-like TME associated with high T-cell density [2] and suppressed angiogenesis [3,4].Cellular transcriptional memory is reported in cell lines after repeated exposure to IFN-γ in vitro [5], suggesting that a Th1-like TME may also exert stable imprinting effects in vivo.Here, we investigated whether TME-dependent transcriptional imprinting in TECs from CRC patients can be exploited to retrieve clinically relevant signatures predicting outcomes.TECs, corresponding normal endothelial cells (NECs), peripheral blood mononuclear cells (PBMCs) and tumor cells were isolated from CRC patients with a favorable Th1-or a worse Control-(non-Th-1)-TME and analyzed by multi-omics analyses to identify differentially expressed genes (DEGs) with parallel epigenetic and/or genomic alterations (methods given in Supplementary Material).Respective DEGs were validated, and their clinical impact was analyzed (Figure 1A).Guanylate-binding protein (GBP)-1, an established marker of an angiostatic Th1-TME Abbreviations: 5-Aza, 5-Aza-2'-deoxycytidine; CCDC80, coiled-coil domain containing 80; COL12A1, collagen type XII alpha 1 chain; CRC, colorectal cancer; DDR2, discoidin domain receptor tyrosine kinase 2; DEGs, differenital expressed genes; DFS, disease-free survival; DNA, desoxyribonucleic acid; ECs, endothelial cells; GBP, guanylate binding protein; HLA-DRA/-DPB1/-DQB1/-DQA1, major histocompatibility complex, class II-DR alpha/DP beta 1/DQ beta 1/DQ alpha 1; IFN, interferon; LIFR, leukemia inhibitory factor receptor; LRMP, lymphoid restricted membrane protein; NECs, normal endothelial cells; MERTK, MER proto-oncogene, tyrosine kinase; Pat, patient; PBMCs, peripheral blood mononuclear cells; PDGFRB, platelet derived growth factor receptor beta; SNX10, sorting nexin 10; STC2, stanniocalcin 2; SPARCL1, secreted protein acidic and cysteine rich like 1; TECs, tumor endothelial cells; TGFB2, transforming growth factor beta 2; Th, T helper; TME, tumor microenvironment; VE-cadherin, vascular endothelial-cadherin.
Discovery, validation, and prodrug design of an ACE2 activator for treating bacterial infection-induced lung inflammation
Authors: Peng Lu, Faith Leslie, Han Wang, Anjali Sodhi, Chang-yong Choi, Andrew Pekosz, Honggang Cui, Hongpeng Jia
Journal: Journal of Controlled Release (2023)

Exacerbated inflammatory responses can be detrimental and pose fatal threats to the host, as exemplified by the global impact of the COVID-19 pandemic, resulting in millions of fatalities. Developing novel drugs to combat the damaging effects of inflammation is essential for both preventive measures and therapeutic interventions. Accumulating evidence suggests that Angiotensin Converting Enzyme 2 (ACE2) possesses the ability to optimize inflammatory responses. However, the clinical applicability of this potential is limited due to the lack of dependable ACE2 activators. In this study, we conducted a screening of an FDA-approved drug library and successfully identified a novel ACE2 activator, termed H4. The activator demonstrated the capability to mitigate lung inflammation caused by bacterial lung infections, effectively modulating neutrophil infiltration. Importantly, to improve the clinical applicability of the poorly water-soluble H4, we developed a prodrug variant with significantly enhanced water solubility while maintaining a similar level of efficacy as H4 in attenuating inflammatory responses in the lungs of mice exposed to bacterial infections. This finding highlights the potential of formulated H4 as a promising candidate for the treatment and prevention of inflammatory diseases, including lung-related conditions.
Seminar: Extracellular Vesicles as Mediators of Environmental Stress in Human Disease
Authors: Vrinda Kalia, Andrea A. Baccarelli, Christine Happel, Jonathan A. Hollander, Anne Marie Jukic, Kimberly A. McAllister, Ramkumar Menon, Bruce A. Merrick, Aleksander Milosavljevic, Lingamanaidu V. Ravichandran, Matthew E. Roth, Anita Subramanian, Frederick L. Tyson, Leroy Worth, Daniel T. Shaughnessy
Journal: Environmental Health Perspectives (2023)

Background: Extracellular vesicles (EVs), membrane-bound particles containing a variety of RNA types, DNA, proteins, and other macromolecules, are now appreciated as an important means of communication between cells and tissues, both in normal cellular physiology and as a potential indicator of cellular stress, environmental exposures, and early disease pathogenesis. Extracellular signaling through EVs is a growing field of research for understanding fundamental mechanisms of health and disease and for the potential for biomarker discovery and therapy development. EVs are also known to play important roles in mediating the effects of exposure to environmental stress. Objectives: This seminar addresses the application of new tools and approaches for EV research, developed in part through the National Institutes of Health (NIH) Extracellular RNA Communication Program, and reflects presentations and discussions from a workshop held 27–28 September 2021 by the National Institute of Environmental Health Sciences (NIEHS) and the National Center for Advancing Translational Sciences (NCATS) on “Extracellular Vesicles, Exosomes, and Cell-Cell Signaling in Response to Environmental Stress.” The panel of experts discussed current research on EVs and environmental exposures, highlighted recent advances in EV isolation and characterization, and considered research gaps and opportunities toward identifying and characterizing the roles for EVs in environmentally related diseases, as well as the current challenges and opportunities in this field. Discussion: The authors discuss the application of new experimental models, particularly organ-on-chip (OOC) systems and in vitro approaches and how these have the potential to extend findings in population-based studies of EVs in exposure-related diseases. Given the complex challenges of identifying cell-specific EVs related to environmental exposures, as well as the general heterogeneity and variability in EVs in blood and other accessible biological samples, there is a critical need for rigorous reporting of experimental methods and validation studies. The authors note that these efforts, combined with cross-disciplinary approaches, would ensure that future research efforts in environmental health studies on EV biomarkers are rigorous and reproducible. https://doi.org/10.1289/EHP12980
Incidence of Type 1 Diabetes in Relation to Exposure to Rotavirus Infections in Pre- and Postvaccine Birth Cohorts in Finland
Authors: Anna Parviainen, Anna But, Reijo Sund, Martti Arffman, Heli Siljander, Mikael Knip
Journal: Diabetes Care (2023)

To explore the incidence of type 1 diabetes in children in relation to exposure to rotavirus infections.A nationwide register-based ecological study on the 1995-2015 birth cohorts in Finland compared those born before and after the national implementation of the rotavirus vaccine in 2009.When the prevaccine 2001-2005 birth cohorts were compared with the postvaccine birth cohorts, the number of children exposed to rotavirus infection by the age of 5 years decreased from 2,522 per 100,000 children (2.5%) to 171 per 100,000 children (0.2%), while the incidence of type 1 diabetes in those aged <5 years decreased from 71.5 to 54.4 per 100,000 person-years (incidence rate ratio 0.79, 95% CI 0.71-0.86).At the population level, a decrease in exposure to rotavirus infections was associated with a decrease in the incidence of type 1 diabetes in young children.
Error in Results
Journal: JAMA Network Open (2023)

Emilie Gaiffe, PhD; Dewi Vernerey, PhD; Laurent Bardiaux, MD; Franck Leroux, BSc; Aurelia Meurisse, BSc; Jamal Bamoulid, MD, PhD; Cecile Courivaud, MD, PhD; Philippe Saas, PharmD, PhD; Marc Hazzan, MD, PhD; Pierre Tiberghien, MD, PhD; Didier Ducloux, MD, PhD
Higher TP53BP2 expression is associated with HBsAg loss in peginterferon-α-treated patients with chronic hepatitis B
Authors: Guiwen Guan, Ting Zhang, Jing Ning, Changyu Tao, Na Gao, Zhenzhen Zeng, Huili Guo, Chia-Chen Chen, Jing Yang, Jing Zhang, Weilin Gu, Ence Yang, Ren Liu, Xiaosen Guo, Shan Ren, Lin Wang, Guochao Wei, Sujun Zheng, Zhiliang Gao, Xinyue Chen, Fengmin Lu, Xiangmei Chen
Journal: Journal of Hepatology (2023)

Background & AimsHBsAg loss is only observed in a small proportion of patients with chronic hepatitis B (CHB) who undergo interferon treatment. Investigating the host factors crucial for CHB functional cure can aid in identifying individuals who would benefit from Peginterferon-alpha (Peg-IFNα) therapy.MethodsWe conducted a Genome-wide association study (GWAS) by enrolling 48 CHB patients with HBsAg loss and 47 with HBsAg persistence after Peg-IFNα treatment. In the validation stage, we included a total of 224 samples, out of which 90 achieved HBsAg loss, to validate the identified significant SNPs. To verify the functional involvement of candidate genes identified, we performed a series of in vitro and in vivo experiments.ResultsGWAS results indicated a significant association between the rs7519753 C allele and serum HBsAg loss in CHB patients after Peg-IFNα treatment (P = 4.85 × 10-8, OR = 14.47). This association was also observed in two independent validation cohorts. eQTL analysis revealed higher hepatic TP53BP2 expression in individuals carrying the rs7519753 C allele (P = 2.90 × 10-6). Liver biopsy RNA-seq from patients with CHB after Peg-IFNα treatment revealed that hepatic TP53BP2 level in the HBsAg loss group was significantly higher compared to the HBsAg persistence group (P = 0.035). In vitro and in vivo experiments demonstrated that loss of TP53BP2 decreased interferon-stimulated genes (ISGs) level and the anti-HBV effect of IFN-α. Mechanistically, TP53BP2 was found to downregulate SOCS2, thereby facilitating JAK/STAT signaling.ConclusionRs7519753 C allele is associated with an increased probability of serum HBsAg loss in patients with CHB post-Peg-IFNα treatment and elevated hepatic TP53BP2 expression. TP53BP2 enhances the response of the hepatocyte to IFN-α by suppressing SOCS2 expression.Impact and implicationsChronic Hepatitis B (CHB) remains a global public health issue. Although current antiviral therapies are more effective in halting disease progression, only a few patients achieve functional cure for hepatitis B with HBsAg loss, highlighting the urgent need for a cure for CHB. This study revealed that the SNP rs7519753 C allele, which is associated with high expression of hepatic TP53BP2, significantly increases the likelihood of serum HBsAg loss in CHB patients undergoing Peg-IFNα therapy. This finding not only provides an exciting predictor for HBsAg loss but identifies a potential therapeutic target for Peg-IFNα treatment. We believe our results are of great interest to a wide range of stakeholders, including patients and patient organizations, the medical community, academia, the life science industry, and the general public.
Transfer learning enhanced graph neural network for aldehyde oxidase metabolism prediction and its experimental application
Authors: Jiacheng Xiong, Rongrong Cui, Zhaojun Li, Wei Zhang, Runze Zhang, Zunyun Fu, Xiaohong Liu, Zhenghao Li, Kaixian Chen, Mingyue Zheng
Journal: Acta Pharmaceutica Sinica B (2023)

Aldehyde oxidase (AOX) is a molybdoenzyme that is primarily expressed in the liver and is involved in the metabolism of drugs and other xenobiotics. AOX-mediated metabolism can result in unexpected outcomes, such as the production of toxic metabolites and high metabolic clearance, which can lead to the clinical failure of novel therapeutic agents. Computational models can assist medicinal chemists in rapidly evaluating the AOX metabolic risk of compounds during the early phases of drug discovery and provide valuable clues for manipulating AOX-mediated metabolism liability. In this study, we developed a novel graph neural network called AOMP for predicting AOX-mediated metabolism. AOMP integrated the tasks of metabolic substrate/non-substrate classification and metabolic site prediction, while utilizing transfer learning from
Anti-osteosarcoma trimodal synergistic therapy using NiFe-LDH and MXene nanocomposite for enhanced biocompatibility and efficacy
Authors: Yani Xu, Lan Yang, Min Li, Haozhou Shu, Na Jia, Yunzhen Gao, Rongying Shi, Xiaojia Yang, Zhirong Zhang, Ling Zhang
Journal: Acta Pharmaceutica Sinica B (2023)

Osteosarcoma is usually resistant to immunotherapy and, thus primarily relies on surgical resection and high-dosage chemotherapy. Unfortunately, less invasive or toxic therapies such as photothermal therapy (PTT) and chemodynamic therapy (CDT) generally failed to show satisfactory outcomes. Adequate multimodal therapies with proper safety profiles may provide better solutions for osteosarcoma. Herein, a simple nanocomposite that synergistically combines CDT, PTT, and chemotherapy for osteosarcoma treatment was fabricated. In this composite, small 2D NiFe-LDH flakes were processed into 3D hollow nanospheres via template methods to encapsulate 5-Fluorouracil (5-FU) with high loading capacity. The nanospheres were then adsorbed onto larger 2D Ti3C2 MXene monolayers and finally shielded by bovine serum albumin (BSA) to form 5-FU@NiFe-LDH/Ti3C2/BSA nanoplatforms (5NiTiB). Both in vitro and in vivo data demonstrated that the 5-FU induced chemotherapy, NiFe-LDH driven chemodynamic effects, and MXene-based photothermal killing collectively exhibited a synergistic "all in one" anti-tumor effect. 5NiTiB improved tumor suppression rate from <5% by 5-FU alone to ∼80.1%. This nanotherapeutic platform achieved higher therapeutic efficacy with a lower agent dose, thereby minimizing side effects. Moreover, the composite is simple to produce, enabling the fine-tuning of dosages to suit different requirements. Thus, the platform is versatile and efficient, with potential for further development.
Maintaining sidedness and fluidity in cell membrane coatings supported on nano-particulate and planar surfaces
Authors: Sidi Liu, Yuanfeng Li, Linqi Shi, Jian Liu, Yijin Ren, Jon D. Laman, Henny C. van der Mei, Henk J. Busscher
Journal: Bioactive Materials (2023)

Supported cell membrane coatings meet many requirements set to bioactive nanocarriers and materials, provided sidedness and fluidity of the natural membrane are maintained upon coating. However, the properties of a support-surface responsible for maintaining correct sidedness and fluidity are unknown. Here, we briefly review the properties of natural membranes and membrane-isolation methods, with focus on the asymmetric distribution of functional groups in natural membranes (sidedness) and the ability of molecules to float across a membrane to form functional domains (fluidity). This review concludes that hydrophilic sugar-residues of glycoproteins in the outer-leaflet of cell membranes direct the more hydrophobic inner-leaflet towards a support-surface to create a correctly-sided membrane coating, regardless of electrostatic double-layer interactions. On positively-charged support-surfaces however, strong, electrostatic double-layer attraction of negatively-charged membranes can impede homogeneous coating. In correctly-sided membrane coatings, fluidity is maintained regardless of whether the surface carries a positive or negative charge. However, membranes are frozen on positively-charged, highly-curved, small nanoparticles and localized nanoscopic structures on a support-surface. This leaves an unsupported membrane coating in between nanostructures on planar support-surfaces that is in dual-sided contact with its aqueous environment, yielding enhanced fluidity in membrane coatings on nanostructured, planar support-surfaces as compared with smooth ones.